This invention relates to indole derivatives of the general formula: 
wherein
R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl or phenylalkyl;
R2 is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl;
R3 is hydrogen, alkyl; and
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl, or phenylalkyl;
and pharmaceutically acceptable acid addition salts of these compounds.
The above compounds are novel and possess valuable antibiotic properties. They can be used in the control and prevention of infectious diseases. In particular, they exhibit a pronounced antibacterial activity, including multi-resistant gram-positive strains, such as Streptococcus pneumoniae and Staphylococcus aureus. These compounds can also be administered in combination with known antibacterially active substances and then exhibit a synergistic effect. Typical combination partners are, e.g., sulfonamides, which can be admixed with the compounds of formula I or their salts in various ratios.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and their use as therapeutically active substances; medicaments based on these substances, optionally in combination with sulfonamides, and their production; the use of these substances as medicaments and for the production of antibacterially active medicaments; as well as the manufacture of the compounds of formula I and their pharmaceutically acceptable salts and intermediates for their manufacture.
The residues named above are defined below. In combined residues such as cycloalkylalkyl etc. the exemplification is to be understood accordingly.
The term xe2x80x9cHalogenxe2x80x9d denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The term xe2x80x9cAlkylxe2x80x9d denotes a straight chained or branched group which carries up to and including 6, preferably 4 carbon atoms, if not otherwise specified. Such groups are, e.g., methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or t-butyl.
xe2x80x9cAlkenyl xe2x80x9d and xe2x80x9calkynylxe2x80x9d denote unsaturated straight chain or branched hydrocarbon groups which carry up to and including 6, preferably 4 carbon atoms, having at least one double or one triple bond, respectively, e.g., vinyl, 2-propenyl, 1,3-butadienyl, isopropenyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl.
xe2x80x9cCycloalkylxe2x80x9d denotes a cyclic hydrocarbon group which carries 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
xe2x80x9cCycloalkylalkylxe2x80x9d denotes the combination of cycloalkyl and alkyl as defined above, e.g., cyclopropylmethyl, 2-cyclopropylethyl, cyclopentylmethyl.
xe2x80x9cAlkanoylxe2x80x9d denotes the formyl group or an alkyl-CO-group, where xe2x80x9calkylxe2x80x9d is as defined above.
xe2x80x9cHeterocyclylxe2x80x9d refers to heterocyclic, saturated 3 to 6 membered rings containing one or two heteroatoms selected from nitrogen, oxygen and sulfur, e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl, or 1,4-dioxo-8-aza-spiro[4.5]decan-8-yl etc., the heterocyclic group may be substituted by one or more substituents such as alkyl, alkoxy, halogen, alkanoyl or phenyl. xe2x80x9cPhenylxe2x80x9d refers to unsubstituted phenyl and phenyl substituted by one or more substituents such as alkyl, alkoxy, halogen, alkanoyl or phenyl.
Preferred compounds of formula I are the compounds wherein R1 is alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, particularly isopropylsulfonyl, isobutyl-sulfonyl, sec-butylsulfonyl, cyclopropylsulfonyl or cyclopropylmethylsulfonyl. Preferred meanings for R2 are hydrogen or alkyl, particularly methyl. Preferred meanings for R3 are hydrogen or methyl. Preferred meanings for R4 is alkyl, particularly ethyl.
Preferred compounds of formula I are:
cyclopropyl-methanesulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
2-methyl-propane-1-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
rac-butane-2-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-1H-indol-4-yl ester;
cyclopropyl-methanesulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-3-methyl-1H-indol-4-yl ester; and
rac-butane-2-sulfonic acid 6-(2,4-diamino-pyrimidin-5-ylmethyl)-1-ethyl-2-methyl-1H-indol-4-yl ester;
and pharmaceutically acceptable acid addition salts of these compounds.
The compounds of formula I form pharmaceutically acceptable acid addition salts with organic and inorganic acids. Examples of acid addition salts of compounds of formula I are salts with mineral acids, for example hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydriodic acid, sulphuric acid, nitric acid, phosphoric acid and the like, salts with organic sulfonic acids, for example with alkyl- and arylsulfonic acids such as methanesulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid and the like as well as salts with organic carboxylic acids, for example with acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid, ascorbic acid and the like.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured in accordance with the invention by
i) reacting a compound of the general formula: 
xe2x80x83in which R1-R4 have the above significance, and X represents a leaving group, with guanidine or a salt thereof, or
ii) introducing at least one of the groups R1, R2 and R4 in a compound of the general formula: 
xe2x80x83in which R3 is as above and R1A, R2A and R4A are as R1, R2 and R4 but at least one, thereof is hydrogen,or
iii) converting a compound of formula I into a pharmaceutically acceptable salt.
The cyclization of the starting materials II (where the xe2x95x90CHX group can be either in (E)- or (Z)-configuration) with guanidine or a salt thereof in accordance with variant i) of the process in accordance with the invention is preferably carried out in an inert organic solvent, preferably in a lower alkanol, e.g., ethanol, or in dimethyl sulfoxide, tetrahydrofuran or dioxane, and at about 50 to 100xc2x0 C. The guanidine is preferably used as a salt, e.g.) as the hydrochloride, in which case the reaction is preferably carried out in the presence of a base, e.g., potassium t-butylate. The leaving group X is preferably bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy.
Variant ii) of the process in accordance of the invention contains several alternatives. A phenyl or heterocyclyl group R2 can be introduced by reacting a compound of the general formula: 
with a compound of the general formula:
R21xe2x80x94Yxe2x80x83xe2x80x83IV
in which
R1, R3 and R4 have the above significance,
R21 is phenyl (which may be substituted)
one of the symbols X and Y represent a leaving group and the other is a group which is eliminated with this leaving group.
In this reaction groups X and Y can be:
X=bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenyl-sulfonyloxy or p-tolylsulfonyloxy; and
Y=(OH)2Bxe2x80x94.
This reaction with a boronic acid derivative IV, also known as a xe2x80x9cSuzuki couplingxe2x80x9d, is preferably effected in an inert organic solvent such as, e.g., dioxane, tetrahydrofuran or dimethyl sulfoxide at a temperature between about 20xc2x0 C. and the boiling point of the reaction mixture. Preferably, a base such as an alkali metal carbonate, e.g., potassium carbonate, is preferably added as well as a catalyst, preferably a palladium complex such as tetrakistriphenylphosphine-palladium.
A compound IV with Y=xe2x80x94Sn(lower-alkyl)3, e.g., xe2x80x94Sn(CH3)3 or xe2x80x94Sn(n-butyl)3 (xe2x80x9cStille reactionxe2x80x9d); xe2x80x94MgHal (xe2x80x9cGrignard couplingxe2x80x9d); or xe2x80x94ZnHal and Hal=chlorine, bromine or iodine (xe2x80x9cNegishi couplingxe2x80x9d) can be used in the above reaction as the reaction partner of formula IV. No base is used in this reaction, although the catalyst described above is preferably used. It can also be advantageous to add an inert salt, especially lithium chloride.
The aforementioned reaction can also be carried out with interchanged substituents X and Y, e.g., with X=xe2x80x94Sn(CH3)3, xe2x80x94MgHal or xe2x80x94ZnHal and Y=bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy. The reaction conditions are essentially the same.
Further methods for introducing R2 are halogenation, alkanoylation, amino-methylation and conversion of the aminomethyl group to methyl, all according to methods disclosed below as process steps (p), (r), (s) and (t).
Groups R1 and R4 can be introduced by reacting a compound of the general formulas: 
with a compound of the general formula:
R1Z or R4Z, respectively,
in which R1-R4 are as defined above and Z is a leaving group.
The leaving group Z, in the case of an alkylation reaction, is preferably bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolyl-sulfonyloxy. For a sulfonylation reaction Z is preferably chlorine. The reaction is preferably carried out in a polar aprotic solvent such as N,N-dimethylformamide and in the presence of a base, e.g., potassium tert-butoxide, at a temperature of about xe2x88x9220xc2x0 C. to 20xc2x0 C.
The manufacture of the pharmaceutically acceptable acid addition salts of the compounds of formula I in accordance with variant iii) can be effected in a manner known per se, e.g., by reacting a compound of formula I with an organic or inorganic acid in an organic solvent such as ethanol, methanol or acetone. The temperature at which the salt formation is carried out is not critical. It generally lies at room temperature, but can also be lower or higher, for example in the range of 0xc2x0 C. to +50xc2x0 C.
Various possibilities for synthesising the compounds of the general formula I are outlined in the following reaction schemes 1-6. 
In Schemata 1-6 the symbols are defined as follows:
R1, R2, R3, and R4 are as defined above;
R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl or phenylalkyl;
R6 represents a suitable protecting group, especially 2-trimethylsilanyl-ethoxymethyl;
R7 represents a suitable protecting group, especially 2-trimethylsilanyl-ethoxymethyl, benzyl or a derivative thereof;
R8 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl or phenylalkyl;
R9 represents a suitable protecting group, especially tetrahydropyran-2-yl or a derivative thereof;
R10 represents a suitable protecting group, especially alkylsulfonyl, phenylsulfonyl, or a derivative thereof;
R11 is aryl, heterocyclyl;
R12 is hydrogen, alkyl;
R13 is dialkylamino including nitrogen-containing heterocycles, which are attached through a nitrogen atom, especially morpholin-4-yl and thiomorpholin-4-yl.
The reaction steps (a)-(t) are preferably carried out as follows:
(a) Alkylation of the hydroxyl of a 1H-indol-4-ol. This reaction is carried out with a compound of the general formula R5xe2x80x94X, where X is a leaving group, preferably Br, in a polar aprotic solvent such as N,N-dimethylformamide and in the presence of a base, preferably potassium tert-butylate, at about 0-30xc2x0 C.
(b) Reduction of the ester function of a methyl 1H-indole 6-carboxylate to the corresponding alcohol. This reaction is carried out using an excess of an aluminum hydride, especially diisobutylaluminumhyride, in a solvent such as tetrahydrofuran, at about 0-20xc2x0 C.
(c) Oxidation of the alcohol group of a [1H-indol-6-yl]-methanol to the corresponding aldehyde. This reaction is carried out using an excess of manganese dioxide in a solvent such as dichloromethane, at temperatures between 0xc2x0 C. and the boiling point of the solvent.
(d) Protection of the 1H-indole nitrogen. This reaction is carried out with a compound of the formula R6xe2x80x94X, where X is a leaving group, e. g., Cl, in the presence of base, preferably potassium tert-butylate, in a polar solvent such as N,N-dimethylformamide, at about 0-30xc2x0 C.
(e) Transformation of a 1H-indole-6-carbaldehyde to a 5-(1H-indol-6-ylmethyl)-2,4,diaminopyrimidine. This two-step sequence is performed by (e1) base-catalyzed condensation of the 1H-indole-6-carbaldehyde with 3-anilinopropionitrile and, (e2) subsequent treatment of the 1-anilino-2-(1H-indol-6-ylmethyl)acrylonitrile formed with guanidine, applying a method described in patent DE2443682.
(f) Cleavage of the 1H-indole nitrogen protective group, R6. This reaction is preferably carried out with tetrabutylammonium fluoride in tetrahydrofuran, in the presence of ethylenediamine and molecular sieves, at temperatures between 20xc2x0 C. and the boiling point of the solvent.
(g) Functionalization of the 1H-indole nitrogen. This reaction is carried out with a compound of the formula R8xe2x80x94X (in the case of an alkylation reaction) or R14xe2x80x94Cl (in the case of a sulfonation reaction), in a polar aprotic solvent such as N,N-dimethylformamide and in the presence of a base, e. g., potassium tert-butoxide, at temperatures between xe2x88x9220xc2x0 C. and 20xc2x0 C. X is a leaving group, preferably Br, and R14 is alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, or N-cycloalkyl-N-alkylsulfamoyl.
(h) Functionalization of the 1H-indole nitrogen. This reaction is carried out with a compound of the formula or R8xe2x80x94X, in a polar aprotic solvent such as N,N-dimethyl-formamide and in the presence of a base, e. g., potassium tert-butoxide, at temperatures between xe2x88x9220xc2x0 C. and 20xc2x0 C. X is a leaving group, preferably Br.
(i) Cleavage of the phenol protecting group, R7. This reaction is carried out,
(i1) in the case R7=2-trimethylsilanyl-ethoxymethyl, either by tetrabutylammonium fluoride in tetrahydrofuran, or by a strong acid, such as sulfuric acid, in a lower alcohol, at temperatures between 0xc2x0 C. and the boiling point of the solvent;
(i2) in the case R7=benzyl, by catalytic hydrogenation using hydrogen and palladium on activated charcoal, in a lower alcohol or a low alkanecarboxylic acid, at about 0-50xc2x0 C., preferably at room temperature.
(j) Functionalization of the hydroxyl of a 1H-indol-4-ol. This reaction is carried with a compound of the formula or R8xe2x80x94X (in the case of an alkylation reaction) or R14xe2x80x94Cl (in the case of a sulfonation reaction), in a polar aprotic solvent such as N,N-dimethyl-formamide and in the presence of a base, e. g., potassium tert-butoxide, at temperatures between xe2x88x9220xc2x0 C. and 20xc2x0 C. X is a leaving group, preferably Br, and R14 is as defined above.
(k) Protection of the hydroxyl of a 1H-indol-6-ylmethanol. This reaction is carried out using 3,4-dihydro-2H-pyran and a catalytic amount of pyridinium toluene-4-sulfonate, in a solvent such as dichloromethane, at about room temperature.
(l) Protection of the nitrogen of a 1H-indole. This reaction is carried out with a suitable sulfonyl chloride, R10xe2x80x94Cl, preferably benzenesulfonyl chloride, at about 0-50xc2x0 C., in a two-phase mixture of aqueous alkali hydroxide and dichloromethane, in the presence of a phase-transfer catalyst such as tetrabutylammonium hydrogensulfate.
(m) Alkylation of a N(1)-protected 1H-indole at C.(2). This reaction is carried out by deprotonation with tert-butyllithium in a solvent such as tetrahydrofuran and subsequent treatment of the 2-lithioindole formed with a compound of the formula R3xe2x80x94X, where X is a leaving group, e.g., I.
(n) Cleavage of the hydroxyl protective group, R9. This reaction is carried out in a lower alcohol such as ethanol using a catalytic amount of pyridinium toluene-4-sulfonate, at temperatures between about 30xc2x0 C. and the boiling point of the solvent.
(o) Cleavage of the nitrogen protecting group of a 1H-indole, R10. This reaction is carried out by hydrolysis in aqueous base, at temperatures between 20xc2x0 C. and the boiling point of the solvent, where water miscible organic solvents such as lower alcohols and/or tetrahydrofuran are added for increased solubility.
(p) Bromination of a 1H-indole at C(3). This reaction is preferably carried out using elemental bromine in a solvent such as N,N-dimethylformamide, at about 0-40xc2x0 C.
(q) Coupling reaction of a 3-bromo-1H-indole with a boronic acid, R11xe2x80x94B(OH)2 (Suzuki coupling). This reaction is carried out preferably in an inert solvent such as 1,2-dimethoxyethane, at temperatures between about 20xc2x0 C. and the boiling point of the solvent. The reaction also requires a base, preferably an alkali carbonate, such as potassium carbonate, and a catalytic amount of a palladium complex such as tetrakis(triphenylphosphine)palladium(0).
(r) Alkanoylation of a 1H-indole at C(3). This reaction is preferably carried out by the Vilsmeier method, using an N,N-disubstituted alkanamide, e.g., N,N-dimethylformamide, and phosphorus oxychloride as reagents and the same N,N-dialkylalkanamide as the solvent at a temperature of about 0-80xc2x0 C.
(s) Aminomethylation of a 1H-indole at C(3). This reaction is carried out by the Mannich method, using a tertiary amine, e. g., morpholine, and formaldehyde as reagents, in a mixture of water and a low alkanecarboxylic acid, e. g., acetic acid, at about 0-80xc2x0 C.
(t) Conversion of a 3-(aminomethyl)-1H-indole to a 3-methyl-1H-indole. This reaction is carried out by catalytic hydrogenation using hydrogen and palladium on activated charcoal, in a lower alcohol, at about 0-50xc2x0 C., preferably at room temperature.
As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts possess valuable antibacterial properties. They are active against a large number of pathogenic microorganisms such as, e.g., Staphylococcus aureus, Streptococcus pneumoniae etc. by virtue of their action in inhibiting bacterial dihydrofolate reductase (DHFR).
The inhibition of the enzyme was taken as a measurement for the antibacterial activity. It is determined using the method of Baccanari and Joyner (Biochemistry 20,1710 (1981)); see also P. G. Hartman et al., FEB. 242, 157-160 (1988).
The IC50 values (concentration at which the enzyme is inhibited to 50%) are determined graphically.
The following Tables 1 and 2 contain inhibitory concentrations determined in the above test for representative members of the class of compound defined by formula I. The following microorganisms were tested:
Col. 1: MIC Spn ATCC 49619; xcexcg/ml (Streptococcus pneumoniae ATCC 49619, trimethoprim- and penicillin-susceptible, reference strain, obtained from American Type Culture Collection).
Col. 2: MIC Spn1/1; xcexcg/ml (Streptococcus pneumoniae 1/1, Trimethoprim- and Penicillin-resistant, Serotype 6; clinical isolate, stored at xe2x88x9280xc2x0 C.). Lit.: H. Locher et al., Can. J. Infect. Dis. 6: Suppl. C, p 469C.
Col. 3: DHFR Spn1/1; xcexcM)xe2x80x94the IC50-values in xcexcM against the purified DHFR of the above strain Spn1/1; of Streptococcus pneumoniae. 
The products in accordance with the invention can be used as medicaments, e.g., in the form of pharmaceutical preparations for enteral or parenteral administration. The products in accordance with the invention can be administered, for example, perorally, e.g., in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g., in the form of suppositories, or parenterally, e.g., in the form of injection solutions. The invention thus also relates to a method of prophylaxis and/or therapeutic treatment of infectious diseases which comprises administering a compound of formula I or pharmaceutically acceptable acid additional salt thereof alone or in combination with a sulfonamide.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the substances in accordance with the invention, if desired in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants.
Not only inorganic carrier materials, but also organic carrier materials are suitable as such carrier materials. Thus, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as carrier materials for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
The usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, flavorants, salts for varying the osmotic pressure, buffers, coating agents and antioxidants come into consideration as pharmaceutical adjuvants.
For parenteral administration the compounds of formula I and, respectively their salts are preferably provided as lyophilizates or dry powders for dilution with conventional carriers such as water or isotonic saline.
As already mentioned, the compounds of formula I and their salts have antibacterial activity. They inhibit bacterial dihydrofolate reductase and potentiate the antibacterial activity of sulfonamides such as, e.g., sulfisoxazole, sulfadimethoxine, sulfamethoxazole, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 2-sulfanilamido-4,5-dimethyl-pyrimidine or sulfaquinoxaline, sulfadiazine, sulfamonomethoxine, 2-sulfanilamido-4,5-dimethyl-isoxazole and other inhibitors of enzymes which are involved in folic acid biosynthesis, such as, e.g., pteridine derivatives.
Oral, rectal and parenteral administration come into consideration for the treatment of hosts, especially warm-blooded hosts, e.g., in human medicine, with the compounds of formula I or combinations thereof with sulfonamides. A daily dosage of about 0.2 g to about 2 g of a compound of formula I in accordance with the invention comes into consideration for adults. When administered in combination with antibacterial sulfon-amides the ratio of compound I to sulfonamide can vary within a wide range; it amounts to, e.g., between 1:40 (parts by weight) and 1:1 (parts by weight); 1:10 to 1:1 are preferred ratios. Thus, e.g., a tablet can contain 80 mg of a compound I in accordance with the invention and 400 mg of sulfamethoxazole, a tablet for children can contain 20 mg of a compound I in accordance with the invention and 100 mg of sulfamethoxazole; syrup (per 5 ml) can contain 40 mg of compound I and 200 mg of sulfamethoxazole.
The compounds of formula I are characterized by a high antibacterial activity and, respectively, a pronounced synergistic effect in combination with sulfonamides and good tolerance.